Male-pronuclei-specific granulin facilitates somatic cells reprogramming via mitigating excessive cell proliferation and enhancing lysosomal function.

Critical reprogramming factors resided predominantly in the oocyte or male pronucleus can enhance the efficiency or the quality of induced pluripotent stem cells (iPSCs) induction. However, few reprogramming factors exist in the male pronucleus had been verified. Here, we demonstrated that granulin (Grn), a factor enriched specifically in male pronucleus, can significantly improve the generation of iPSCs from mouse fibroblasts. Grn is highly expressed on Day 1, Day 3, Day 14 of reprogramming induced by four Yamanaka factors and functions at the initial stage of reprogramming. Transcriptome analysis indicates that Grn can promote the expression of lysosome-related genes, while inhibit the expression of genes involved in DNA replication and cell cycle at the early reprogramming stage. Further verification determined that Grn suppressed cell proliferation due to the arrest of cell cycle at G2/M phase. Moreover, ectopic Grn can enhance the lysosomes abundance and rescue the efficiency reduction of reprogramming resulted from lysosomal protease inhibition. Taken together, we conclude that Grn serves as an activator for somatic cell reprogramming through mitigating cell hyperproliferation and promoting the function of lysosomes.

Ferroptosis: a critical mechanism of N6-methyladenosine modification involved in carcinogenesis and tumor progression.

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation. It occurs when multiple redox-active enzymes are ectopically expressed or show abnormal function. Hence, the precise regulation of ferroptosis-related molecules is mediated across multiple levels, including transcriptional, posttranscriptional, translational, and epigenetic levels. N6-methyladenosine (m6A) is a highly evolutionarily conserved epigenetic modification in mammals. The m6A modification is commonly linked to tumor proliferation, progression, and therapy resistance because it is involved in RNA metabolic processes. Intriguingly, accumulating evidence suggests that dysregulated ferroptosis caused by the m6A modification drives tumor development. In this review, we summarized the roles of m6A regulators in ferroptosis-mediated malignant tumor progression and outlined the m6A regulatory mechanism involved in ferroptosis pathways. We also analyzed the potential value and application strategies of targeting m6A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

Rodent models of AKI and AKI-CKD transition: an update in 2024.

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In the past decade, rodent models have been developed and used to mimic different etiologies of acute kidney injury (AKI), AKI to chronic kidney disease (CKD) transition or progression, and AKI with comorbidities. These models have been applied for both mechanistic research and preclinical drug development. However, current rodent models have their limitations, especially since they often do not fully recapitulate the pathophysiology of AKI in human patients, and thus need further refinement. Here, we discuss the present status of these rodent models, including the pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, and their main limitations. Future efforts should focus on establishing robust models that simulate the major clinical and molecular phenotypes of human AKI and its progression.

HIF-1 contributes to autophagy activation via BNIP3 to facilitate renal fibrosis in hypoxia in vitro and UUO in vivo.

The molecular basis of renal interstitial fibrosis, a major pathological feature of progressive kidney diseases, remains poorly understood. Autophagy has been implicated in renal fibrosis, but whether it promotes or inhibits fibrosis remains controversial. Moreover, it is unclear how autophagy is activated and sustained in renal fibrosis. The present study was designed to address these questions using the in vivo mouse model of unilateral ureteral obstruction and the in vitro model of hypoxia in renal tubular cells. Both models showed the activation of hypoxia-inducible factor-1 (HIF-1) and autophagy along with fibrotic changes. Inhibition of autophagy with chloroquine reduced renal fibrosis in unilateral ureteral obstruction model, whereas chloroquine and autophagy-related gene 7 knockdown decreased fibrotic changes in cultured renal proximal tubular cells, supporting a profibrotic role of autophagy. Notably, pharmacological and genetic inhibition of HIF-1 led to the suppression of autophagy and renal fibrosis in these models. Mechanistically, knock down of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a downstream target gene of HIF, decreased autophagy and fibrotic changes during hypoxia in BUMPT cells. Together, these results suggest that HIF-1 may activate autophagy via BNIP3 in renal tubular cells to facilitate the development of renal interstitial fibrosis.NEW & NOTEWORTHY Autophagy has been reported to participate in renal fibrosis, but its role and underlying activation mechanism is unclear. In this study, we report the role of HIF-1 in autophagy activation in models of renal fibrosis and further investigate the underlying mechanism.

Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ-/- mice displayed reduced tumor progression compared to wild types, with increased response to anti-PD-1. Tumors from PKCδ-/- mice demonstrated TH1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ-/- mice. Coinjection of PKCδ-/- M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ+/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy.

Myeloid PFKFB3-mediated glycolysis promotes kidney fibrosis.

Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby's group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3 ΔMϕ ) and their wild type littermates (Pfkfb3 WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3 ΔMϕ mice compared to Pfkfb3 WT mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3 ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.

Efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19: a systematic review and meta-analysis.

OBJECTIVES: Several clinical trials have evaluated the efficacy and safety of baricitinib in COVID-19 patients. Recently, there have been reports on critical patients, which are different from previous research results. The meta-analysis was performed to investigate the effects of baricitinib in COVID-19, by pooling data from all clinically randomized controlled trials (RCTs) available to increase power to testify. METHODS: Studies were searched in PubMed, Embase, and Cochrane Library databases on January 31, 2023. We performed a meta-analysis to estimate the efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19. This study is registered with INPLASY, number 202310086. RESULTS: A total of 3010 patients were included in our analyses. All included studies were randomized controlled trials or prospective study. There was no difference in 14-day mortality between the two groups [OR 0.23 (95% CI 0.03-1.84), I2 = 72%, P = 0.17]. In subgroup analyses we found that baricitinib did not seem to improve significantly in 24-day mortality critically ill patients [OR 0.60 (95% CI 0.35-1.02), I2 = 0%, P = 0.06]. Fortunately, baricitinib have led to faster recovery and shorter hospital stays for COVID-19 patients. There were no difference in infections and infestations, major adverse cardiovascular events, deep vein thrombosis and pulmonary embolism. CONCLUSIONS: Baricitinib did not increase the incidence of adverse reactions. At the same time, we can find that it reduces the mortality of COVID-19 patients, not including the critically ill.

Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery.

Low molecular weight heparin (LMWH) is often used to prevent perioperative venous thrombosis after surgery, but aspirin is also recommended by academics. Studies were searched in electronic databases until February 24, 2023. We performed a meta-analysis to evaluate the safety and efficacy of aspirin and LMWH for venous thromboembolism (VTE) prophylaxis in patients after orthopedic surgery. The outcomes were death from any causes, deep vein thrombosis (DVT), pulmonary embolism (PE), etc. This study was registered with INPLASY, number 202320117. Six randomized controlled trials enrolled 13,851 patients with postoperative joint surgery. The risk of DVT was comparable between the two groups when aspirin was combined with mechanical devices (RR 0.61 [95% CI 0.27-1.39], I² = 62%, P = 0.24). No significant differences in all cause death, PE, wound infection, and wound complication were found between the aspirin and LMWH groups. In this meta-analysis, the mortality rate was comparable between the aspirin and LMWH groups. However, aspirin alone had a higher risk of DVT than LMWH. Based on the results of this meta-analysis, we suggest aspirin combined with mechanical devices for VTE prophylaxis in patients after orthopedic surgery.

Extravasation of Blood and Blood Toxicity Drives Tubular Injury from RBC Trapping in Ischemic AKI.

Red blood cell (RBC) trapping is common in ischemic acute kidney injury (AKI) and presents as densely packed RBCs that accumulate within and engorge the kidney medullary circulation. In this study, we tested the hypothesis that "RBC trapping directly promotes tubular injury independent of extending ischemia time." Studies were performed on rats. Red blood cell congestion and tubular injury were compared between renal arterial clamping, venous clamping, and venous clamping of blood-free kidneys. Vessels were occluded for either 15 or 45 min with and without reperfusion. We found that RBC trapping in the medullary capillaries occurred rapidly following reperfusion from renal arterial clamping and that this was associated with extravasation of blood from congested vessels, uptake of blood proteins by the tubules, and marked tubular injury. To determine if this injury was due to blood toxicity or an extension of ischemia time, we compared renal venous and arterial clamping without reperfusion. Venous clamping resulted in RBC trapping and marked tubular injury within 45 min of ischemia. Conversely, despite the same ischemia time, RBC trapping and tubular injury were minimal following arterial clamping without reperfusion. Confirming the role of blood toward tubular injury, injury was markedly reduced in blood-free kidneys with venous clamping. Our data demonstrate that RBC trapping results in the rapid extravasation and uptake of blood components by tubular cells, causing toxic tubular injury. Tubular toxicity from extravasation of blood following RBC trapping appears to be a major component of tubular injury in ischemic AKI, which has not previously been recognized.

PFKFB3-Mediated Glycolysis Boosts Fibroblast Activation and Subsequent Kidney Fibrosis.

Renal fibrosis, a hallmark of chronic kidney diseases, is driven by the activation of renal fibroblasts. Recent studies have highlighted the role of glycolysis in this process. Nevertheless, one critical glycolytic activator, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), remains unexplored in renal fibrosis. Upon reanalyzing the single-cell sequencing data from Dr. Humphreys' lab, we noticed an upregulation of glycolysis, gluconeogenesis, and the TGFß signaling pathway in myofibroblasts from fibrotic kidneys after unilateral ureter obstruction (UUO) or kidney ischemia/reperfusion. Furthermore, our experiments showed significant induction of PFKFB3 in mouse kidneys following UUO or kidney ischemia/reperfusion. To delve deeper into the role of PFKFB3, we generated mice with Pfkfb3 deficiency, specifically in myofibroblasts (Pfkfb3f/f/PostnMCM). Following UUO or kidney ischemia/reperfusion, a substantial decrease in fibrosis in the injured kidneys of Pfkfb3f/f/PostnMCM mice was identified compared to their wild-type littermates. Additionally, in cultured renal fibroblast NRK-49F cells, PFKFB3 was elevated upon exposure to TGFß1, accompanied by an increase in α-SMA and fibronectin. Notably, this upregulation was significantly diminished with PFKFB3 knockdown, correlated with glycolysis suppression. Mechanistically, the glycolytic metabolite lactate promoted the fibrotic activation of NRK-49F cells. In conclusion, our study demonstrates the critical role of PFKFB3 in driving fibroblast activation and subsequent renal fibrosis.

WD repeat domain 82 (Wdr82) facilitates mouse iPSCs generation by interfering mitochondrial oxidative phosphorylation and glycolysis.

BACKGROUND: Abundantly expressed factors in the oocyte cytoplasm can remarkably reprogram terminally differentiated germ cells or somatic cells into totipotent state within a short time. However, the mechanism of the different factors underlying the reprogramming process remains uncertain. METHODS: On the basis of Yamanaka factors OSKM induction method, MEF cells were induced and reprogrammed into iPSCs under conditions of the oocyte-derived factor Wdr82 overexpression and/or knockdown, so as to assess the reprogramming efficiency. Meanwhile, the cellular metabolism was monitored and evaluated during the reprogramming process. The plurpotency of the generated iPSCs was confirmed via pluripotent gene expression detection, embryoid body differentiation and chimeric mouse experiment. RESULTS: Here, we show that the oocyte-derived factor Wdr82 promotes the efficiency of MEF reprogramming into iPSCs to a greater degree than the Yamanaka factors OSKM. The Wdr82-expressing iPSC line showed pluripotency to differentiate and transmit genetic material to chimeric offsprings. In contrast, the knocking down of Wdr82 can significantly reduce the efficiency of somatic cell reprogramming. We further demonstrate that the significant suppression of oxidative phosphorylation in mitochondria underlies the molecular mechanism by which Wdr82 promotes the efficiency of somatic cell reprogramming. Our study suggests a link between mitochondrial energy metabolism remodeling and cell fate transition or stem cell function maintenance, which might shed light on the embryonic development and stem cell biology.

Hypermethylation suppresses microRNA-219a-2 to activate the ALDH1L2/GSH/PAI-1 pathway for fibronectin degradation in renal fibrosis.

Epigenetic regulations, such as DNA methylation and microRNAs, play an important role in renal fibrosis. Here, we report the regulation of microRNA-219a-2 (mir-219a-2) by DNA methylation in fibrotic kidneys, unveiling the crosstalk between these epigenetic mechanisms. Through genome-wide DNA methylation analysis and pyro-sequencing, we detected the hypermethylation of mir-219a-2 in renal fibrosis induced by unilateral ureter obstruction (UUO) or renal ischemia/reperfusion, which was accompanied by a significant decrease in mir-219a-5p expression. Functionally, overexpression of mir-219a-2 enhanced fibronectin induction during hypoxia or TGF-ß1 treatment of cultured renal cells. In mice, inhibition of mir-219a-5p suppressed fibronectin accumulation in UUO kidneys. ALDH1L2 was identified to be the direct target gene of mir-219a-5p in renal fibrosis. Mir-219a-5p suppressed ALDH1L2 expression in cultured renal cells, while inhibition of mir-219a-5p prevented the decrease of ALDH1L2 in UUO kidneys. Knockdown of ALDH1L2 enhanced PAI-1 induction during TGF-ß1 treatment of renal cells, which was associated with fibronectin expression. In conclusion, the hypermethylation of mir-219a-2 in response to fibrotic stress attenuates mir-219a-5p expression and induces the up-regulation of its target gene ALDH1L2, which may reduce fibronectin deposition by suppressing PAI-1.

Two tripartite classification systems of CD86+ and CD206+ macrophages are significantly associated with tumor recurrence in stage II-III colorectal cancer.

Introduction: The prognostic value of tumor-associated macrophages remains unclear in colorectal cancer (CRC). Two tripartite classification systems, namely, ratio and quantity subgroups, were investigated as the prognostic stratification tools for stage II-III CRC. Methods: We assessed the infiltration intensity of CD86+ and CD206+ macrophages in 449 cases with stage II-III disease by immunohistochemical staining. Ratio subgroups were defined by the lower- and upper-quartile points of CD206+/(CD86++CD206+) macrophage ratio, including the low-, moderate-, and high-ratio subgroups. Quantity subgroups were defined by the median points of CD86+ and CD206+ macrophages and included the low-, moderate-, and high-risk subgroups. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Results: Ratio subgroups (RFS/OS: HR=2.677/2.708, all p<0.001) and quantity subgroups (RFS/OS: HR=3.137/3.250, all p<0.001) could serve as independent prognostic indicators that effectively predicted survival outcomes. More importantly, log-rank test revealed that patients in the high-ratio (RFS/OS: HR=2.950/3.151, all p<0.001) or high-risk (RFS/OS: HR=3.453/3.711, all p<0.001) subgroup exhibited decreased survival outcomes after adjuvant chemotherapy. The predictive accuracy of the quantity subgroups within 48 months was higher than that of the ratio subgroups and tumor stage (all p<0.05). Conclusions: Ratio and quantity subgroups could serve as independent prognostic indicators that could potentially be incorporated into the tumor staging algorithm to improve prognostic stratification and provide better predictions of survival outcomes in stage II-III CRC after adjuvant chemotherapy.

PHB3 Is Required for the Assembly and Activity of Mitochondrial ATP Synthase in Arabidopsis.

Mitochondrial ATP synthase is a multiprotein complex, which consists of a matrix-localized F1 domain (F1-ATPase) and an inner membrane-embedded Fo domain (Fo-ATPase). The assembly process of mitochondrial ATP synthase is complex and requires the function of many assembly factors. Although extensive studies on mitochondrial ATP synthase assembly have been conducted on yeast, much less study has been performed on plants. Here, we revealed the function of Arabidopsis prohibitin 3 (PHB3) in mitochondrial ATP synthase assembly by characterizing the phb3 mutant. The blue native PAGE (BN-PAGE) and in-gel activity staining assays showed that the activities of ATP synthase and F1-ATPase were significantly decreased in the phb3 mutant. The absence of PHB3 resulted in the accumulation of the Fo-ATPase and F1-ATPase intermediates, whereas the abundance of the Fo-ATPase subunit a was decreased in the ATP synthase monomer. Furthermore, we showed that PHB3 could interact with the F1-ATPase subunits ß and δ in the yeast two-hybrid system (Y2H) and luciferase complementation imaging (LCI) assay and with Fo-ATPase subunit c in the LCI assay. These results indicate that PHB3 acts as an assembly factor required for the assembly and activity of mitochondrial ATP synthase.

Theoretical and Experimental Investigations on High-Precision Micro-Low-Gravity Simulation Technology for Lunar Mobile Vehicle.

With the development of space technology, the functions of lunar vehicles are constantly enriched, and the structure is constantly complicated, which puts forward more stringent requirements for its ground micro-low-gravity simulation test technology. This paper puts forward a high-precision and high-dynamic landing buffer test method based on the principle of magnetic quasi-zero stiffness. Firstly, the micro-low-gravity simulation system for the lunar vehicle was designed. The dynamic model of the system and a position control method based on fuzzy PID parameter tuning were established. Then, the dynamic characteristics of the system were analyzed through joint simulation. At last, a prototype of the lunar vehicle's vertical constant force support system was built, and a micro-low-gravity landing buffer test was carried out. The results show that the simulation results were in good agreement with the test results. The sensitivity of the system was better than 0.1%, and the constant force deviation was 0.1% under landing impact conditions. The new method and idea are put forward to improve the micro-low-gravity simulation technology of lunar vehicles.

TeCVP: A Time-Efficient Control Method for a Hexapod Wheel-Legged Robot Based on Velocity Planning.

Addressing the problem that control methods of wheel-legged robots for future Mars exploration missions are too complex, a time-efficient control method based on velocity planning for a hexapod wheel-legged robot is proposed in this paper, which is named time-efficient control based on velocity planning (TeCVP). When the foot end or wheel at knee comes into contact with the ground, the desired velocity of the foot end or knee is transformed according to the velocity transformation of the rigid body from the desired velocity of the torso which is obtained by the deviation of torso position and posture. Furthermore, the torques of joints can be obtained by impedance control. When suspended, the leg is regarded as a system consisting of a virtual spring and a virtual damper to realize control of legs in the swing phase. In addition, leg sequences of switching motion between wheeled configuration and legged configuration are planned. According to a complexity analysis, velocity planning control has lower time complexity and less times of multiplication and addition compared with virtual model control. In addition, simulations show that velocity planning control can realize stable periodic gait motion, wheel-leg switching motion and wheeled motion and the operation time of velocity planning control is about 33.89% less than that of virtual model control, which promises a great prospect for velocity planning control in future planetary exploration missions.

High Infiltration of CD203c+ Mast Cells Reflects Immunosuppression and Hinders Prognostic Benefit in Stage II-III Colorectal Cancer.

Background: Activated mast cells (AMCs) have been fully researched in inflammation and allergic reactions. However, the protumoral role of AMCs and their biomarker CD203c has not yet been investigated in colorectal cancer (CRC). Methods: We retrospectively collected 449 postoperative patients with stage II-III CRC at two different hospitals as the training (n=310) and validation (n=139) cohorts. These findings were further validated in the independent cohort (Integration of GSE39582 and GSE17536, n=489). The AMC density was assessed using CD203c staining or the CIBERSORT method. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Results: As an independent factor, high AMC infiltration was associated with worse RFS/OS in the training (hazard ratio [HR]=3.437/3.014, all p<0.001) and validation (HR=3.537/2.382, all p<0.001) cohorts. We developed and validated an AMC-based nomogram for better stratification for postoperative recurrence in these two cohorts. The role of AMC density was further validated in the independent cohort. High AMC infiltration was associated with decreased RFS/OS after adjuvant chemotherapy (all p<0.05). Approximately 74.2% of intramural CD203c+ AMCs expressed a high level of PD-L1. Multiple immunosuppressive pathways were enriched in high AMC infiltration tumors, including upregulation of the TNF-α/NF-κB and angiogenesis pathways and downregulation of the IFN-γ and IFN-α responses. AMC infiltration was reversely associated with CD8+ T-cell infiltration (all p<0.05). Conclusion: High AMC infiltration is associated with worse survival outcomes in stages II-III CRC. AMC density may serve as a potential biomarker for survival benefit in patients receiving adjuvant chemotherapy. This AMC-based nomogram could provide better recurrence stratification. Immunosuppression in tumors with high AMC infiltration might contribute to promoting tumor progression.

PFKFB3 mediates tubular cell death in cisplatin nephrotoxicity by activating CDK4.

Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. However, the mechanism of cisplatin nephrotoxicity remains unclear and no effective kidney protective strategies are available. Here, we report the induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in both in vitro cell culture and in vivo mouse models of cisplatin nephrotoxicity. Notably, PFKFB3 was mainly induced in the nucleus of kidney tubular cells, suggesting a novel function other than its canonical role in glycolysis. Both pharmacological inhibition and genetic silencing of PFKFB3 led to the suppression of cisplatin-induced apoptosis in cultured renal proximal tubular cells (RPTCs). Moreover, cisplatin-induced kidney injury or nephrotoxicity was ameliorated in renal proximal tubule-specific PFKFB3 knockout mice. Mechanistically, we demonstrated the interaction of PFKFB3 with cyclin-dependent kinase 4 (CDK4) during cisplatin treatment, resulting in CDK4 activation and consequent phosphorylation and inactivation of retinoblastoma tumor suppressor (Rb). Inhibition of CDK4 reduced cisplatin-induced apoptosis in RPTCs and kidney injury in mice. Collectively, this study unveils a novel pathological role of PFKFB3 in cisplatin nephrotoxicity through the activation of the CDK4/Rb pathway, suggesting a new kidney protective strategy for cancer patients by blocking PFKFB3.

The metabolic pathway regulation in kidney injury and repair.

Kidney injury and repair are accompanied by significant disruptions in metabolic pathways, leading to renal cell dysfunction and further contributing to the progression of renal pathology. This review outlines the complex involvement of various energy production pathways in glucose, lipid, amino acid, and ketone body metabolism within the kidney. We provide a comprehensive summary of the aberrant regulation of these metabolic pathways in kidney injury and repair. After acute kidney injury (AKI), there is notable mitochondrial damage and oxygen/nutrient deprivation, leading to reduced activity in glycolysis and mitochondrial bioenergetics. Additionally, disruptions occur in the pentose phosphate pathway (PPP), amino acid metabolism, and the supply of ketone bodies. The subsequent kidney repair phase is characterized by a metabolic shift toward glycolysis, along with decreased fatty acid ß-oxidation and continued disturbances in amino acid metabolism. Furthermore, the impact of metabolism dysfunction on renal cell injury, regeneration, and the development of renal fibrosis is analyzed. Finally, we discuss the potential therapeutic strategies by targeting renal metabolic regulation to ameliorate kidney injury and fibrosis and promote kidney repair.

Deciphering the vital roles and mechanism of m5C modification on RNA in cancers.

5-methylcytosine (m5C modification) plays an essential role in tumors, which affects different types of RNA, the expression of downstream target genes, and downstream pathways, thus participating in the tumor process. However, the effect of m5C modification on RNA in tumors and the exact mechanism have not been systematically reviewed. Therefore, we reviewed the status and sites of m5C modification, as well as the expression pattern and biological functions of m5C regulators in tumors, and further summarized the effects and regulation mechanism of m5C modification on messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), long non-coding RNA (lncRNA) and other RNA in tumors. Finally, we summed up the interaction network, potential application, and value in clinical diagnosis and treatment of tumors. Taken together, this review benefits revealing the mechanism of m5C modification in tumor progression and provides new strategies for tumor diagnosis and treatment.